2018非小細(xì)胞肺癌egfr突變優(yōu)化患者管理

1、Cáncer de pulmón no microcítico EGFR mutado: Optimización del manejo del paciente,Manuel Cobo DolsOncologia Médica H Regional Universitario Málaga. IBIMA12-4-2018,EGFR TKIs versus Chemothe

2、rapy,,Ongoing Study: erlotinib + bevacizumab vs. erlotinib as first-line treatment,IMPRESS. In exploratory analysis of T790M negative, there may be PFS benefit to continuation of EGFR TKI,Soria JC, et al. Lancet Oncol. 2

3、015;16:990-998.,Mok et al., Phase III (Aura 3) (Osimertinib vs. CT) mPFS 10.1 vs. 4.4 m NEJM 2016,,Girard N. Future oncol 2017,Plasma EGFR T790M,Plasma from AURA trial sent for BEAMingPaired tumor and plasma availab

4、le for 216 patients,Oxnard et al, JCO, 2016,18 T790M+ in plasma, not tumor,,,,111 T790M+ in tumor and plasma,47 T790M+ in tumor, not plasma,40 patients T790M- tumor and plasma,T790M+ in tumor:62% RR, 10m PFS,T790M+ in p

5、lasma:63% RR, 10m PFS,,,Immunotherapy in EGFR-Mutant NSCLC,*Data for the pembrolizumab doses were pooled.,CheckMate 057,KEYNOTE-010*,OAK,Nivolumab,Docetaxel,,Pembrolizumab,Docetaxel,,Atezolizumab,Docetaxel,,References i

6、n slidenotes.,,1.0,,,,0.5,,2.0,,0.25,,4.0,,1.0,,,,0.1,,,,10,,1.0,,,,0.2,,,,2,,,,,LBA2_PR: Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA),Key results,Ramalingam S et al.

7、 Ann Oncol 2017;28(suppl 5):Abstr LBA2_PR,Median PFS, months (95%CI),18.9 (15.2, 21.4),10.2 (9.6, 11.1),HR 0.46,(95%CI 0.37, 0.57)p<0.0001,Osimertinib,SoC,PFS,1.0,0.6,0.4,0.2,0.0,0,3,6,9,12,15,18,21,24,27,0.8,Probabi

8、lity of progression-free survival,Time from randomization, months,No. at risk,Osimertinib,SoC,279,262,233,210,178,139,0,71,26,4,277,239,197,152,107,78,37,10,2,0,,,,,,Favours SoC,SubgroupOverall (n=556)Log Rank (primar

9、y)Cox PHSex Male (n=206) Female (n=350)Age at screening<65 (n=298)≥65 (n=258)RaceAsian (n=347)Non-Asian (n=209)Smoking history Yes (n=199)No (n=357)CNS metastasesYes (n=116)No (n=440)WHO pe

10、rformance status0 (n=228)1 (n=327)EGFR mutation at randomisation#Exon 19 deletion (n=349) L858R (n=207)EGFR mutation by ctDNA?Positive (n=359)Negative (n=124)Centrally confirmed EGFR mutation§Positive

11、 (n=500)Negative (n=6)¶,,FLAURA data cut-off: 12 June 2017Hazard ratio <1 implies a lower risk of progression on osimertinib 80 mg. Size of circle is proportional to the number of events*By Investigator assess

12、ment; #Local or central test; ?Result missing for 36 patients in the osimertinib arm and 37 patients in the SoC arm; §Result missing for 21 patients in the osimertinib arm and 29 patients in the SoC arm; ¶Subgr

13、oup categories with less than 20 events were excluded from the analysisCNS, central nervous system; ctDNA, circulating tumour DNA; EGFR, epidermal growth factor receptor; PFS, progression-free survival; SoC, standard-of

14、-care; WHO, World Health Organization. Ramalingam et al. Presented at :ESMO Congress Sep 8-12,, 2017; Madrid, Spain.,PFS* across subgroups,,,0.1,,,,,,,,,,0.2,0.3,0.4,0.6,0.8,Hazard ratio (95% confidence interval)0.46

15、 (0.37, 0.57)0.46 (0.37, 0.57)0.58 (0.41, 0.82)0.40 (0.30, 0.52)0.44 (0.33, 0.58)0.49 (0.35, 0.67)0.55 (0.42, 0.72)0.34 (0.23, 0.48) 0.48 (0.34, 0.68)0.45 (0.34, 0.59)0.47 (0.30, 0.74)0.46 (0.36, 0.59)0

16、.39 (0.27, 0.56)0.50 (0.38, 0.66) 0.43 (0.32, 0.56)0.51 (0.36, 0.71)0.44 (0.34, 0.57)0.48 (0.28, 0.80)0.43 (0.34, 0.54)NC (NC, NC),2.0,PFS hazard ratio and 95% confidence interval,1.0,Favours osimertinib,,10.0,

17、,25,,,Objective response rate*,FLAURA data cut-off: 12 June 2017Tick marks indicate censored data *By investigator assessment #Analysis performed using a logistic regression stratified by race (Asian versus Non-Asian)

18、and mutation type (Exon 19 deletion versus L858R); ?Response did not require confirmation; §Calculated using Kaplan-Meier approachCI, confidence interval; DoR, duration of response; ORR, objective response rate; So

19、C, standard-of-care. Ramalinagm et al. Presented at :ESMO Congress Sep 8-12,, 2017; Madrid, Spain.,Duration of response,Median DoR, months (95% CI) 17.2 (13.8, 22.0) 8.5 (7.3, 9.8),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

20、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Probability of remaining in response,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,3,6,9,12,15,18,21,24,27,Time from first response (months),No. at riskOsimer

21、tinibSoC,,Osimertinib,SoC,,,26,Key results (cont.),Ramalingam S et al. Ann Oncol 2017;28(suppl 5):Abstr LBA2_PR,No. at risk,Osimertinib,SoC,279,276,269,253,243,232,0,154,87,4,277,263,252,237,218,200,126,64,1,0,29,24,OS

22、interim analysis,1.0,0.6,0.4,0.2,0.0,0,3,6,9,12,15,18,21,24,27,0.8,30,Probability of overall survival,Time from randomization, months,HR 0.63,(95%CI 0.45, 0.88)p=0.0068?,?A p-value of <0.0015 was required forstatist

23、ical significance at current maturity,Median overall survival,Not reached,Osimertinib,SoC,Not reached,LBA2_PR: Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA),Girard N.

24、Future oncol 2017,Paciente,Tumor,Edad,PS,Comorbilidad,Cercanía domicilo a hospital,Apoyo familiar,Sintomática /asintomático,Carga tumoral,Localización / Nº mtsPosibilidad antiangiogénicos?,

25、Mts SNC,Subtipo mutación,Decisión de tratamiento en primera línea. Factores a tener en cuenta,Afatinib in NSCLC Pts With Uncommom EGFR Mutations,Yang JC, et al. Lancet Oncol. 2015;16:830-838.,*Consists of

26、pts with all point mutations or duplications in exons 18-21. ?Consists of pts with de novo T790M mutations. ?Consists of pts with exon 20 insertions. §Consists of pts with mutations falling into groups 1/2/3 (n = 18

27、/3/2).,Pacientes con PS 2 ó mayor,,Juan O. Therapeutic Advances in Medical Oncology 2017,Pacientes unfit, suelen ser 30% de los casos Ensayos con afatinib, dacometinib o osimertinib, no han reclutado pts PS 2El

28、resto de estudios, con erlotinib y gefitinib la proporción de pts PS 2 fue pequeña (excepto en el EURTAC con erlotinib se reclutaron 14% de pts con PS 2)[Rosell et al. Lancet Oncol 2012]..- Pacientes PS 2: lo

29、más recomendado gefitinib y erlotinib. Más datosAfatinib y dacometinib son más tóxicosSólo un estudio prospectivo fase II con gefitinib que reclutó 30 pts con mutación de EGFR, ineleg

30、ible para quimioterapia. 22 pts de ellos tenían PS ? 3, y 68% de ellos, el PS regresó a PS 1 en el curso de 1 mes, con una RG del &%% PFS 6,5 meses y SG de 18,8 mesesTener en cuenta el tipo de comorbilida

31、d (Ej. Problemas intestinales crónicos, TKIs 2º generación menos recomendados. Hepática: más toxicidad con gefitinib, etc)Erlotinib y gefitinib tienen más interacción farmacológic

32、a. gefitinib y erlotinib tienen un potencial importante de interacción con otros fármacos. Se comportan como inductores o inhibidores de enzimas relacionadas con los citocromos,Juan O. Therapeutic Advances in

33、Medical Oncology 2017,Pacientes unfit- ancianos dependientes/polimedicados,PFS benefit in AURA3 patients with CNS metastases at baseline,Mok et al. NEJM 2017,Osimertinib (n=22)#,SoC (n=19),Median best percentage change

34、from baseline in CNS target lesion size: -64% (range -100% to +20%),Median best percentage change from baseline in CNS target lesion size: -45% (range -100% to +20%),Best change from baseline in target lesion size (%),,,

35、,,,,,,,,,,,,,,,,,,-100,-80,-60,-40,-20,0,20,,,,,,,,,,,,,,,,,,,,,,,,-100,-80,-60,-40,-20,0,20,Best change from baseline in target lesion size (%),FLAURA: CNS RESPONSE*: CNS EVALUABLE FOR RESPONSE SET,R,R,R,R,R,R,R,R,R,R,R

36、,R,R,R,R,R,R Prior brain radiotherapy,R Prior brain radiotherapy,36,Presented by J Vansteenkiste at ESMO Asia 2017, 17–19 November 2017, Singapore Proferred Paper Session 1, Abstract LBA5. Ann Oncol 2017;28 (suppl_

37、10): mdx729.007,Osimertinib aun no aprobado en 1º línea de CPNM avanzado con mutación EGFR,Flaura. CNS PFS: CNS FULL ANALYSIS SET. Osimertinib is the recomendation in pts with SNC metastases,*Progression e

38、vents that did not occur within 2 scheduled visits (plus visit window) of the last evaluable assessment (or randomisation) were censored and therefore excluded in the number of events; #A p-value of <0.0015 was requir

39、ed for statistical significance at current maturityCI, confidence interval; CNS, central nervous system; HR, hazard ratio; NC, not calculable; PFS, progression-free survival; SoC, standard-of-careFLAURA data cut-off: 1

40、2 June 2017,Median CNS PFS, months (95% CI) NC (16.5, NC) 13.9 (8.3, NC),CNS PFS was nominally statistically significantCNS PFS analysis was third in the hierarchical statistical testing strategy and, as

41、 OS did not reach formal statistical significance (HR 0.63 [95% CI 0.45, 0.88]; p=0.0068),# CNS PFS could not be formally tested for statistical significance,No. at riskOsimertinibSoC,Presented by J Vansteenkiste at ES

42、MO Asia 2017, 17–19 November 2017, Singapore Proferred Paper Session 1, Abstract LBA5. Ann Oncol 2017;28 (suppl_10): mdx729.007,Osimertinib aun no aprobado en 1º línea de CPNM avanzado con mutación EGFR,

43、First line,Second line,Third and sucessive lines,First generation TKIErlotinib Or gefitinib,Second generation TKIAfatinib,TKI + angiangiogenicErlotinib + bevacizumab,Third generation TKIOsimertinib,Chemoterapy,9-10 m

44、,,15-30% no possible 2º line,11-13 m Afatin,Second generation TKIDacometinib,14,7 m Dacomet,16 m erl + bev,E + B T790M - ultsens,10 m erl + bev,E + B T790M + ultsens,16 m erl + bev,18,9 m osimertinib,Osimert T

45、790M - ultsens,Osimert T790M + ultsens,?????????????,?????????????,5,5-6 m,25-30% T790M not detected: NotPossible biopsy. Liquid biopsy false negative,Osi + GefitT790M + C797Strans,9-10 m,QTT790M + C797SCis,5,5 m,S

46、equential cronograma,CRITICAL QUESTION.When appoved, Osimertinib for all patients in first line EGFR mut, OR sequence has sense in a subgroup of patients?,First line,Second line,Third and sucessive lines,First generatio

47、n TKIErlotinib Or gefitinib,Second generation TKIAfatinib,TKI + angiangiogenicErlotinib + bevacizumab,Third generation TKIOsimertinib,Chemoterapy,9-10 m,,15-30% no possible 2º line,11-13 m Afatin,Second generati

48、on TKIDacometinib,14,7 m Dacomet,16 m erl + bev,E + B T790M - ultsens,10 m erl + bev,E + B T790M + ultsens,16 m erl + bev,18,9 m osimertinib,Osimert T790M - ultsens,Osimert T790M + ultsens,?????????????,???????????

49、??,5,5-6 m,25-35% T790M not detected: NotPossible biopsy. Liquid biopsy false negative,Sequential cronograma,Which is the more recomendable treatment in first line EGFR mut ???Is based on PFS or is based in the overal

50、l survival of the complete potential sequence ?,Osimertinib: up to first?,Presented By Sanjay Popat at 2017 ASCO Annual Meeting,.- Add median survivals: WRONGThis is not biological real. It is play with numbers,.- “Osim

51、ertinib first line: no other target therapies in sucessive lines. Best, use sequence: WRONG. If the treatment is clearly benefit, this must be the first line,Subsequent therapies post-afatinib among patients with EGFRM+

52、NSCLC in LUX-Lung 3, 6 and 7,Single-agent CT,Other?,1st-gen TKI monotherapy*,Any subs systemic treatment,Platinum-based CT,Second-line treatment,394(71%),252(46%),39(7%),49(9%),54(10%),Third-line treatment,2

53、65(48%),48(9%),104(19%),75(14%),38(7%),Fourth-line treatment,156(28%),27(5%),50(9%),49(9%),30(5%),,Any-line treatment,394(71%),277(50%),181(33%),186(34%),Discontinued afatinib at time of analysis,Patients

54、 with common EGFR mutations randomised to afatinib,n=579,n=553,121(22%),,,,,,*Erlotinib, gefitinib and icotinib; ?Includes: platinum-based, single-agent and other CT combination therapies; osimertinib, afatinib, HM6171

55、3 and rociletinib monotherapies; erlotinib-, gefitinib-, icotinib- and afatinib-containing combinations; immune checkpoint inhibitors; and ‘other’ therapies,Sequist L et al., ESMO 2017 poster #1349,Data cut-off (LL3 &am

56、p;6: 25 March 2016; LL7: 05 December 2016),,29 % of patients notReceived subsequent therapy for differenten reasons:This patients loose the chance to received 2º line therapy againstT790M mut,,,,,,,,,Non-Shedd

57、ing DNAs,Shedding DNAs,,Vessels, Tissue Barriers,TissueBiopsy,LiquidBiopsy,,Tumor Heterogeneity,All EGFRmut contain actEGFRmutBut only some contain resistant T790M,Not all tumor cells shed DNA to blood,,,,Presented b

58、y : James Chih-Hsin Yang, MD, PhD. National Taiwan University,Not always Liquid biopsy detect T790M. 67-75% false negative,These patients loose chance to received Osimertinib in second line,L781Q ? no treatment opti

59、on,1.Thress KS, et al. Nat Med. 2015;21:560-562. 2.Niederst MJ, et al. Clin Cancer Res. 2015;21:3924-3933. 3.Hidaka N et al., Lung Cancer, 2017 4. Ho, C-C et al., JTO . 12 (3): 567-572, 20175. Bersanelli M et a

60、l. J Thorac Oncol. 2016;11:e121-123.,6. Kim TM, et al. J Thorac Oncol. 2015;10:1736-1744. 7. Planchard D et al. Annals of Onc 2015;26:2073-2078. 8. Li L et al. Oncotarget. 2017.9. Ou S-HI et al. Lung Canc

61、er 2017: 228-23110 .Piotrowska Z et al., ASCO 201711. Ercan D. et al., Can Res 2015, 21:3913-3923,Unknown driver ? no treatment option,Unknown driver ? Rechallenge with 3rd gen TKI might be beneficial,Investigational c

62、ompounds,unknown driver ? no treatment option,BRAF V600E ? BRAF inhibitor,C797S/T790M cis (most frequent)3: ? no treatment option,C797S/T790M trans2: ? combination of TKIsC797S/T790M wt: ?Retained sensitivity to 1st and

63、 2nd -gen TKIs11,,Mechanisms of Acquired Resistance to Osimertinib: Driver Mutation, Potential Targeted Therapy Option,Lost T790M:48%,Potential Strategies at Osimertinib resistance:,Adapted form Niederst et al. CCR 2015

64、. Preclinical data,EGFRmNSCLC,Sensitive EGFR mut,First, Second Generation TKI,Third Generation Osimertinib Resistance: Re-biopsy,Sensitive EGFR mut, T790M,Sensitive to 1-2G TKIs,Sensitive to 1G + 3G TKI,Resistant toT

65、KIs_Chemo,,29%,Most frequent,20%,Allelic disposition,Courtesy N. Reguart,9/12,Genomic landscape of EGFR C797S in lung cancer ctDNA, Presented by Zofia Piotrowska,Frequency of co-occurring mutations in C797S+ samples,51/6

66、1 (84%) pts had at least one bona fide resistance mechanism co-occurring with C797S,,Piotrowska Z. IASLC 2017 Tokio,The question: Although osimertinib in first line increase PFS because target clones with T790M from the

67、beguining OR RELAPSE THE APARITION OF T790M AS THE FIRST RESISTANCE MECHANISM, could induce more agressive fenotypes in the progession and short the overall survival in many patients?,Rosenbloom et al. / Biochimica et B

68、iophysica Acta 1867 (2017) 69–83,.- Competition between sensitive and resistant strains. The fitness landscape of drug-resistant strains, as well as the timing of drug resistance mutations, can determine the outcome of t

69、herapy. Sometimes the two subclones have equal fitness in the absence of drug OR sometimes the resistant subclone pays a fitness “cost” and is less fit than the sensitive clone .- C: The drug resistance mutation occur

70、s early, allowing the resistant clone to grow to a large size by the time therapy begins. As a result, the slight decrease in tumor size caused by therapy may go undetected, and the tumor may be deemed intrinsically resi

71、stant to therapy. D: The drug resistance mutation occurs late, and the resistant clone is small at the time of treatment. Substantial time may pass before the tumor regrows. The tumor is deemed to acquire resistance du

72、ring therapy, .- E Drug resistance mutations occur multiple times before therapy, but cannot grow substantially due to the fitness cost. If a resistance mutation occurs near the time that treatment begins, elimination